6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinic acid | 639091-33-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinic acid
• 英文别名: 6-[4-(3-Fluoro-benzyloxy)-phenoxy]-nicotinic acid；6-[4-[(3-fluorophenyl)methoxy]phenoxy]pyridine-3-carboxylic acid
• CAS: 639091-33-1
• 化学式: C₁₉H₁₄FNO₄
• 分子量: 339.323
• InChiKey: NLSVNZNNRUDEFB-UHFFFAOYSA-N

物化性质

• 沸点：
  518.0±50.0 °C(Predicted)
• 密度：
  1.332±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  68.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinic acid 在 water-soluble carbodiimide *HCl 、 铁粉 、 氯化铵 、 1-羟基苯并三唑 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 1.5h， 生成 N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide
  参考文献：
  名称：

  作为一类新型的NCX抑制剂的6- {4-[（3-氟苄基）氧基]苯氧基}烟酰胺衍生物的合成与构效关系：QSAR研究。

  摘要：

  钠钙交换剂（NCX）输送Na +和Ca2 +离子，并控制心肌细胞中Ca2 +的浓度。钙超载是通过激活反向NCX引起的，并导致心力衰竭时的再灌注损伤。因此，NCX是预防和治疗再灌注性心律不齐，心肌挛缩和坏死的有吸引力的靶标。我们已经合成了一系列的6- {4-[（（3-氟苄基）氧基]苯氧基}烟酰胺衍生物，并评估了它们对NCX的反向和正向模式的抑制活性。N-（3-氨基苄基）-6- {4-[（（3-氟苄基）氧基]苯氧基}烟酰胺（8）被证明是反向NCX活性的有效抑制剂，IC50值为0.24 microM。

  DOI：

  10.1016/j.bmc.2004.10.047
• 作为产物：
  描述：

  6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinonitrile 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.5h， 以99%的产率得到6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinic acid
  参考文献：
  名称：

  作为一类新型的NCX抑制剂的6- {4-[（3-氟苄基）氧基]苯氧基}烟酰胺衍生物的合成与构效关系：QSAR研究。

  摘要：

  钠钙交换剂（NCX）输送Na +和Ca2 +离子，并控制心肌细胞中Ca2 +的浓度。钙超载是通过激活反向NCX引起的，并导致心力衰竭时的再灌注损伤。因此，NCX是预防和治疗再灌注性心律不齐，心肌挛缩和坏死的有吸引力的靶标。我们已经合成了一系列的6- {4-[（（3-氟苄基）氧基]苯氧基}烟酰胺衍生物，并评估了它们对NCX的反向和正向模式的抑制活性。N-（3-氨基苄基）-6- {4-[（（3-氟苄基）氧基]苯氧基}烟酰胺（8）被证明是反向NCX活性的有效抑制剂，IC50值为0.24 microM。

  DOI：

  10.1016/j.bmc.2004.10.047

文献信息

• Synthesis and structure–activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium–calcium exchanger
  作者：Takahiro Kuramochi、Akio Kakefuda、Hiroyoshi Yamada、Ippei Sato、Taku Taguchi、Shuichi Sakamoto

  DOI：10.1016/j.bmc.2004.07.038

  日期：2004.10

  nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several

  钠钙交换剂（NCX）被称为控制心肌细胞中Ca（2+）浓度的转运蛋白。在心力衰竭和心肌缺血-再灌注的情况下，NCX是导致心律失常的瞬态内向电流的基础，该电流导致心动过速后的去极化和非折返性延迟。NCX是治疗心力衰竭和心肌缺血-再灌注的有吸引力的靶标。我们基于化合物3设计并合成了一系列苯氧基吡啶衍生物。已评估了这些衍生物对CCL39细胞中NCX反向和正向模式的抑制活性。我们发现了几种新型的有效NCX抑制剂（39q，48k），它们对反向NCX抑制活性具有很高的选择性。
• Synthesis and structure–activity relationships of benzyloxyphenyl derivatives as a novel class of NCX inhibitors: effects on heart failure
  作者：Takahiro Kuramochi、Akio Kakefuda、Hiroyoshi Yamada、Takashi Ogiyama、Taku Taguchi、Shuichi Sakamoto

  DOI：10.1016/j.bmc.2004.10.048

  日期：2005.2

  In the context of heart failure and myocardial ischemia reperfusion, the activity of the sodium-calcium exchanger can lead to calcium overload, which in turn can lead to contractile dysfunction and arrhythmia. Therefore, NCX is an attractive target for treatment of heart failure and myocardial ischemia reperfusion. We have designed and synthesized a series of benzyloxyphenyl derivatives as potential NCX inhibitors, based on compound 4. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward modes of NCX, and two novel potent NCX inhibitors (7i, 10a) were discovered. Compound 7i was evaluated for its efficacy on ouabain-induced tonotropy and arrhythmia in a heart-failure model. (C) 2004 Elsevier Ltd. All rights reserved.
• Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor
  作者：Takahiro Kuramochi、Akio Kakefuda、Hiroyoshi Yamada、Issei Tsukamoto、Taku Taguchi、Shuichi Sakamoto

  DOI：10.1016/j.bmc.2005.03.052

  日期：2005.6

  Ca2+ overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca2+ overload, because NCX inhibitors can directly inhibit the influx of Ca2+ into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reper-fusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23h) with an IC50 value of 0.12 mu M against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23h are discussed. (c) 2005 Elsevier Ltd. All rights reserved.